This invention relates to peptide derivatives of the formulas [I'] to [IV'] to be shown below and pharmaceutically acceptable acid addition salts thereof which exhibit more potent stimulant activities in central nerve system such as an antagonistic action against hypothermia, a locomoter stimulant action, a spinal reflex stimulant action, etc., as compared with other pharmaceuticals, particularly TRH (thyrotropin releasing hormone) and its derivatives, and thus are useful as a therapeutic medicament for central nervous disorders.
As the compounds relevant to the objective compounds of the present invention, known is L-pyroglutamyl-L-histidyl-L-prolinamide (pGlu-His Pro-NH.sub.2) referred to as TRH (thyrotropin releasing hormone). TRH is known to have TSH (thyrotropin: thyroid stimulating hormone)-releasing activity and is also known to be useful as a therapeutic medicine for disturbance of consciousness caused by cerebral function disturbances. However, TRH has defects such that it is poorly stable in vivo, easily decomposed by pyroglutamylpeptidase, TRH amidase and other enzymes [Progress of Medicines (Igaku no Ayumi), vol. 134, No. 4, p. 252] and deactivated in a short period, necessitating frequent administration when used, which results in excessive secretion of TSH. For the improvement of the above-mentioned defects of TRH, studies from various aspects have been conducted for TRH derivatives which on the one hand reduce TSH secretion-inducing action as the side effect and on the other hand possess more potent central nerve-stimulant actions such as an antihypnotic action, an anti-reserpine action (antagonistic action against hypothermia), a locomoter stimulant action, a spinal reflex stimulant action, a dopamine potentiating action and an anesthesia antagonism, and have more excellent durability in action than TRH. For example, the following reports have been presented.
U.S. Pat. No. 4,100,152 PA1 Japanese Patent Unexamined Publication No. 33197/1986 PA1 Japanese Patent Unexamined Publication No. 22797/1987 PA1 EP 1845 PA1 Japanese Patent Unexamined Publication No. 172996/1985 PA1 GB 1564078 PA1 U.S. Pat. No. 4,788,179 PA1 U.S. Pat. No. 4,636,567 PA1 U.S. Pat. Nos. 4,610,821 and 4,299,821